Oxidative Stress-Mediated Brain Dehydroepiandrosterone (DHEA) Formation in Alzheimer?s Disease Diagnosis

Abstract

Neurosteroids are steroids made by brain cells independently of peripheral steroidogenic sources. The biosynthesis of most neurosteroids is mediated by proteins and enzymes similar to those identified in the steroidogenic pathway of adrenal and gonadal cells. Dehydroepiandrosterone (DHEA) is a major neurosteroid identified in the brain. Over the years we have reported that, unlike other neurosteroids, DHEA biosynthesis in rat, bovine, and human brain is mediated by an oxidative stress-mediated mechanism, independent of the cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1) enzyme activity found in the periphery. This alternative pathway is induced by pro-oxidant agents, such as Fe2+ and β-amyloid peptide. Neurosteroids are involved in many aspects of brain function, and as such, are involved in various neuropathologies, including Alzheimer’s disease (AD). AD is a progressive, yet irreversible neurodegenerative disease for which there are limited means for ante-mortem diagnosis. Using brain tissue specimens from control and AD patients, we provided evidence that DHEA is formed in the AD brain by the oxidative stress-mediated metabolism of an unidentified precursor, thus depleting levels of the precursor in the blood stream. We tested for the presence of this DHEA precursor in human serum using a Fe2+-based reaction and determined the amounts of DHEA formed. Fe2+ treatment of the serum resulted in a dramatic increase in DHEA levels in control patients, whereas only a moderate or no increase was observed in AD patients. The DHEA variation after oxidation correlated with the patients’ cognitive and mental status. In this review, we present the cumulative evidence for oxidative stress as a natural regulator of DHEA formation and the use of this concept to develop a blood-based diagnostic tool for neurodegenerative diseases linked to oxidative stress, such as AD.

Exploring the potential of natural and synthetic neuroprotective steroids against neurodegenerative disorders: A literature review

“…Thus, there is a hope to protect the structure and function of ageing brains through long-term DHEA supplementation. [156][157][158] The possible neuroprotective role of DHEA against the development of AD is also elucidated in experimental models in which the young female rats were ovariectomized and AD was developed by daily intraperitoneal adminis- As reported earlier, neuroinflammation plays a major role in pathogenesis of neurodegenerative disorders. Secretion of inflammatory mediators by activated glial cells and infiltrating leukocytes initiates the neuropathological mechanisms leading to AD, PD, and HD.…”

“…Therefore, the age‐associated decline in DHEA levels may contribute to the pathological amyloid precursor protein processing and eventually lead to the development of AD. Thus, there is a hope to protect the structure and function of ageing brains through long‐term DHEA supplementation …”

Dehydroepiandrosterone (DHEA) and DHEA Sulfate: Roles in Brain Function and Disease

“…Brown and colleagues speculated that the higher concentrations of DHEA in the hippocampus may have been produced by an as-yet-unknown pathway that involved the oxidation of an unknown precursor. This speculation has been given support by the finding that the addition of redox-active ferrous iron to serum samples causes a significant increase in the amount of detectable DHEA [127]. It is also supported by the demonstration that oxidative stress associated with the presence of β-amyloid treatment induces DHEA synthesis in human and rodent cells in vitro [126][127][128][129].…”

“…This speculation has been given support by the finding that the addition of redox-active ferrous iron to serum samples causes a significant increase in the amount of detectable DHEA [127]. It is also supported by the demonstration that oxidative stress associated with the presence of β-amyloid treatment induces DHEA synthesis in human and rodent cells in vitro [126][127][128][129]. In this context, it is interesting that the brain regions containing the higher concentrations of DHEA [126] also have higher burdens of neuritic plaques and β-amyloid immunoreactivity, features that are generally associated with AD progression [130].…”

Do Dehydroepiandrosterone (DHEA) and Its Sulfate (DHEAS) Play a Role in the Stress Response in Domestic Animals?

“…In several rat, bovine, and human brain model systems, DHEA biosynthesis is mediated by an oxidative stress/Fe 2+ , independent of the CYP17A enzyme. This mechanism is not fully understood and it may be typical of pathologic conditions such as ischemia, trauma, or neurodegeneration, which can generate an oxidative environment and increase oxidative stress (72).…”